EGFR in various cancers − Rakyat Biologi

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase found on the plasma membrane of epithelial cells that is involved in initiating growth and proliferation signalling pathways [24]. It is an important proto-oncogene due to its prevalence in several cancers, including NSCLC, breast, prostate and ovarian cancers. NSCLC is of particular significance because of the poor patient survival rates. It has been reported that NSCLC represents 85% of lung cancers [25], which account for one fifth of all cancer-related deaths [26].

Aberrant EGFR activation in these cancers can arise from mutation or overexpression. Nearly 90% of oncogenic EGFR mutations occur in the cytoplasmic kinase domain, and result in its continuous autophosphorylation [27]. The consequence of this is a constitutively active EGFR signalling cascade, through which downstream transcription factors are activated and confer various properties to the cancer phenotype, including angiogenesis, migration, proliferation, stromal invasion and resistance to apoptosis [28]. These EGFR mutations are mostly restricted to NSCLC, and are rare in other cancers. Nevertheless, there is still a high incidence of EGFR overexpression in glioblastomas [29], NSCLC, head and neck squamous cell carcinomas, and colorectal cancer [27].

Yamazaki and coworkers provided initial evidence for the therapeutic potential of targeting EGFR in cancers. They demonstrated that a ribozyme, targeted against an aberrant EGFR, could suppress its expression in the ERM5-1 cell line and significantly reduce their tumorigenic capacity in nude mice [30]. This provided evidence of tumour dependence on EGFR, which was reinforced by the subsequent emergence and clinical success of EGFR-targeted therapies in various cancers [27]. Examples include the small molecule drugs, gefitinib and erlotinib, which inhibit EGFR signalling by competing for ATP-binding sites within its intracellular kinase domain, and initially exhibited great efficacy in NSCLC patients [31, 32]. However, the success of these drugs was short-lived due to the emergence of drug resistance, often acquired by cancers via mutations in the drug-binding site of EGFR [33], thus highlighting the need for new therapeutic strategies against EGFR-dependent cancers.